Protective Effects of Myrtol Standardized Against Radiation-Induced Lung Injury

Zhao, Deyun; Qu, Hongjin; Guo, Jiaming; Zhao, Hainan; Yang, Yue; Zhang, Pei; Cao, Kun; Xiao, Lanbo; Cui, Jianguo; Liu, Cong; Cai, Jian-ming; Gao, Fu; Li, Bailong

doi:10.1159/000438655

Cited by 18 publications

(12 citation statements)

References 49 publications

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“…Lungs of mice received irradiation at a total dose of 20 Gy and a dose rate of 1 Gy/min. The irradiation source was 60 Co from the radiation center (Faculty of Naval Medicine, Second Military Medical University, China) [21, 22]. …”

Section: Methodsmentioning

confidence: 99%

Hypoxia-Induced Mesenchymal Stromal Cells Exhibit an Enhanced Therapeutic Effect on Radiation-Induced Lung Injury in Mice due to an Increased Proliferation Potential and Enhanced Antioxidant Ability

Zhu

et al. 2017

Cell Physiol Biochem

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Background/Aims: Radiation therapy is an important treatment for thoracic cancer; however, side effects accompanied with radiotherapy lead to limited tumor control and a decline in patient quality of life. Among these side effects, radiation-induced lung injury (RILI) is the most serious and common. Hence, an effective remedy for RILI is needed. Mesenchymal stromal cells (MSCs) are multipotent adult stem cells that have been demonstrated to be an effective treatment in some disease caused by tissue damage. However, unlike other injuries, RILI received limited therapeutic effects from implanted MSCs due to local hypoxia and extensive reactive oxygen species (ROS) in irradiated lungs. Since the poor survival of MSCs is primarily due to hypoxia and ROS generation, we hypothesize that persistent and adaptive hypoxia treatment induces enhanced resistance to hypoxic stress in implanted MSC. The aim of this study is to investigate whether persistent and adaptive hypoxia treatment of bmMSCs prior to their transplantation in injured mice enhanced survival and improved curative effects in RILI. Methods: Primary bmMSCs were obtained from the marrow of six-week-old male C57BL6/J mice and were cultured either under normoxic conditions (21% O₂) or hypoxic conditions (2.5% O₂). Mice were injected with normoxia/hypoxia MSCs after thoracic irradiation (20 Gy). The therapeutic effects of MSCs on RILI were assessed by pathological examinations that included H&E staining, Masson staining and α-SMA staining; meanwhile, inflammatory factors were measured using an ELISA. The morphology of MSCs in vitro was recorded using a microscope and identified by flow cytometry, cell viability was measured using the CCK-8 assay, the potential for proliferation was detected by the EdU assay, and ROS levels were measured using a ROS fluorogenic probe. In addition, HIF-1α and several survival pathway proteins (Akt, p-Akt, Caspase-3) were also detected by western blotting. Results: Implanted MSCs alleviated both early radiation-induced pneumonia and late pulmonary fibrosis. However, hypoxia MSCs displayed a more pronounced therapeutic effect compared to normoxia MSCs. Compared to normoxia MSCs, the hypoxia MSCs demonstrated greater cell viability, an enhanced proliferation potential, decreased ROS levels and increased resistance to hypoxia and ROS stress. In addition, hypoxia MSCs achieved higher activation levels of HIF-1α and Akt, and HIF-1α played a critical role in the development of resistance. Conclusion: Hypoxia enhances the therapeutic effect of mesenchymal stromal cells on radiation-induced lung injury by promoting MSC proliferation and improving their antioxidant ability, mediated by HIF-1α.

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Section: Methodsmentioning

confidence: 99%

Hypoxia-Induced Mesenchymal Stromal Cells Exhibit an Enhanced Therapeutic Effect on Radiation-Induced Lung Injury in Mice due to an Increased Proliferation Potential and Enhanced Antioxidant Ability

Zhu

et al. 2017

Cell Physiol Biochem

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“…In the present study, myrtol treatment significantly inhibited the activation of TGF-β1 level in PTKO mice. Zhao et al (13) also observed that myrtol standardized inhibited TGF-β1 expression, and suppressed the levels of TNF-α, IL-1β and IL-6 in radiation-induced lung injury.…”

Section: Discussionmentioning

confidence: 95%

“…Domestic clinical studies have shown that its clinical efficacy is similar to the total curative effect of the import gel myrtol forte group (12). Furthermore, pharmacological and pharmacodynamics studies have demonstrated that myrtol standardized has expectorant anti-inflammatory effects, relieving cough and asthma, and reported reduced toxicity and side-effects (13).…”

Section: Introductionmentioning

confidence: 99%

Myrtol improves post‑traumatic knee osteoarthritis by regulation of reactive oxygen species, transforming growth factor β1 and apoptosis in a mouse model

Duan

Zhang

et al. 2017

Exp Ther Med

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Abstract. The present study tested whether myrtol improves post-traumatic knee osteoarthritis (PTKO) by regulating the reactive oxygen species (ROS), transforming growth factor β1 (TGF-β1) and apoptosis in a mouse model. PTKO model mice were administered with 150, 300 or 450 mg/kg myrtol for 8 weeks. ELISA analysis was used to measure tumor necrosis factor-α, interleukin-6, malondialdehyde, superoxide dismutase, reactive oxygen species and TGF-β1 levels. Caspase-3 and Bax protein expressions were analyzed using western blot analysis. In the current study, treatment with myrtol improved the tissue damage and osteoarthritis score, while it also reversed the subchondral bone thickness, subchondral bone density, trabecular bone volume/relative trabecular bone volume ratio and trabecular bone spacing in PTKO mice. The activity of tumor necrosis factor α, interleukin-6, TGF-β1, malondialdehyde, superoxide dismutase and ROS were effectively inhibited, and the protein expression of caspase-3 and Bax were clearly suppressed by treatment with myrtol in a mouse model of PTKO. In conclusion, the results demonstrated that myrtol treatment improved PTKO through the suppression of inflammation, oxidative stress, ROS, TGF-β1 and Bax/caspase-3 in mice, and myrtol may be a potential agent for clinical therapy. IntroductionPost-traumatic knee osteoarthritis (PTKO) is a common disease presenting joint degenerative changes (1). PTKO is most frequently detected on the elderly population, with an estimated 15 million cases in China (2). Survey data in the United States also demonstrated that PTKO is the second most common cause of disability in males >50 years old, after cardiovascular disease (3). Thus, prevention and treatment of PTKO have become one of the most difficult issues in clinical practice at present (3).Transforming growth factor β1 (TGF-β1) is a member of the TGF-β superfamily and a type of multifunctional polypeptide growth factor (4). It participates in the proliferation and differentiation processes of diversified cell types, such as chondrocytes, epithelial cells and fibroblasts, and has essential regulating effects in the developing process of embryo, organs and cartilage. Studies have demonstrated that, in the chondrocytes of rabbits and cattle, TGF-β1 can regulate the synthesis of proteoglycan (4,5). In addition, TGF-β1 has the ability to promote synthesis of type II collagen by reducing consumption of proteoglycan in order to repair the cartilage (6). Therefore, it can be seen that TGF-β1 serves an important regulatory role in the process of maintaining chondrocytes and cartilage (7).PTKO is a chronic autoimmune disease characterized by joint synovitis, and its early lesion mainly presents on the synovial membrane (8). Synovial cells are subject to rapid proliferation due to autoimmune response resulting from an external stimulus, such as infection or trauma (9); thus, the infiltration of diversified inflammatory cells on the synovial membrane is enhanced (9). In addition, a large number of cytokines, inflammator...

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“…Moreover, the results from previous studies have shown that inhibiting TNF-α and IL-6 could reduce radiation-induced lung fibrosis (33,34). In addition, research from Zhao and colleagues showed that standardized Myrtol could attenuate RILI by inhibiting TNF-α, IL-1β and IL-6 expression (35). Thus, inhibition of these proinflammatory cytokines may protect against the development of RILI in mice.…”

Section: Discussionmentioning

confidence: 97%

α7‑nAchR agonist GTS‑21 reduces radiation‑induced lung injury

et al. 2018

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Radiation-induced lung injury (RILI) is a major complication of thoracic radiotherapy that starts as exudative inflammation and proceeds to lung fibrosis, and additional studies are required to develop methods to ameliorate RILI. The aim of this study was to explore whether the nicotinic acetylcholine receptor subtype-7 (α7-nAChR) agonist GTS-21 has a protective effect against RILI. C57BL6 mice were irradiated with 12 Gy to induce a mouse model of RILI. Some of the mice received an i.p. injection of 4 mg/kg GTS-21 for three days with or without radiation treatment. Mice were sacrificed at 1, 3, 7, 14 and 21 days and at 3 and 6 months after irradiation. The results showed that GTS-21 treatment significantly relieved RILI by decreasing TNF-α, IL-1β and IL-6 production in serum via inhibition of NF-κB activation and downregulation of TLR-4 and HMGB1 expression in the lungs. In addition, we found that GTS-21 may regulate the MMP/TIMP balance in RILI. Finally, we found that GTS-21 inhibited NOX-1 and NOX-2 expression, which subsequently reduced ROS levels and Hif-1α expression in RILI. However, GTS-21 showed little effect on lung tissue without radiation exposure. The results above were also validated in RAW264.7 macrophages. Our results showed that activation of the cholinergic anti-inflammatory pathway via the α7-nAChR agonist GTS-21 reduced RILI. The protective effect of GTS-21 against RILI is partly attributed to inhibition of the HMGB1/TLR4/NF-κB pathway and ROS production. Thus, activation of the α7-nAChR pathway may lead to new possibilities in the therapeutic management of RILI.

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Protective Effects of Myrtol Standardized Against Radiation-Induced Lung Injury

Cited by 18 publications

References 49 publications

Hypoxia-Induced Mesenchymal Stromal Cells Exhibit an Enhanced Therapeutic Effect on Radiation-Induced Lung Injury in Mice due to an Increased Proliferation Potential and Enhanced Antioxidant Ability

Hypoxia-Induced Mesenchymal Stromal Cells Exhibit an Enhanced Therapeutic Effect on Radiation-Induced Lung Injury in Mice due to an Increased Proliferation Potential and Enhanced Antioxidant Ability

Myrtol improves post‑traumatic knee osteoarthritis by regulation of reactive oxygen species, transforming growth factor β1 and apoptosis in a mouse model

α7‑nAchR agonist GTS‑21 reduces radiation‑induced lung injury

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